Signals mediated by the T cell receptor (TCR) regulate both T cell development and the balance between activation and tolerance in both early T cells (thymocytes) and mature T cells. Understanding how TCR signals regulate these processes is essential for understanding autoimmune diseases and designing effective vaccines to pathogens. We are employing genetically modified mice that have distinct alterations in their TCR signaling molecules or in related molecules that feedback on TCR signals. We are investigating how alteration in these signaling structure impact on selection of thymocytes that will subsequently be important in protective immunity. Moreover, we are examining how T cells from such animals differentially mediate T cell functional activities such as cytokine secretion, killing, and proliferation. Finally, we are employing this system to examine how signals through the TCR regulate immune tolerance through mechanisms such as cell death (apoptosis), suppression, and energy. To this end, we are adapting these genetically modified animals to experimental models of autoimmune disease and microbial infection.